Compounds with activity at estrogen receptors

Abstract

Disclosed herein are compounds of Formula I as disclosed herein, methods of modulating the activity of an estrogen receptor and methods of treating a disorder associated with estrogen receptors.

1. A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or metabolite thereof, 
       wherein:
 X is selected from the group consisting of oxygen, sulfur, S═O, and SO 2 ; 
 n is an integer selected from the group consisting of 1, 2, 3 and 4 
 R 20  is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, haloalkyl, perhaloalkyl, sulphonyl, —C(═Z)R 30 , —C(═Z)OR 30 , —C(═Z)NR 31 R 32 , —S(O)NR 31 R 32 , —S(O) 2 NR 31 R 32 , —P(═O)(OR 30 ), and —CH 2 O(C═O)R 30 ; 
 R 1 , R 2 , R 3 , and R 4  are each separately and independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl(C 3-6 cycloalkyl), halogen, C 1-6 haloalkyl, C 1-6 perhaloalkyl, C 1-6 haloalkoxy, —CN, —C(═Z)R 30 , —C(═Z)OR 30 , —C(═Z)NR 31 R 32 , —C(R 30 )═NR 31 , —NR 31 R 32 , —N═CR 31 R 32 , —N(R 30 )—C(═Z)R 30 , —N(R 30 )—C(═Z)NR 31 R 32 , —S(O)NR 31 R 32 , —S(O) 2 NR 31 R 32 , —N(R 30 )—S(═O)R 30 , —N(R 30 )—S(═O) 2 R 30 , —OR 30 ), —SR 30 , and —OC(═Z)R 30 ; wherein said alkyl, alkenyl, alkynyl, cycloalkyl and alkoxy are optionally substituted; 
 or two of R 1 , R 2 , R 3 , and R 4  on adjacent carbons taken together, along with the two intervening carbons to which they are attached, form a C 3-6 cycloalkenyl, aryl, heteroaryl or C 3-6 heterocycloalkenyl group; 
 R 5 , R 6 , R 7 , and R 8  are each separately and independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl(C 3-6 cycloalkyl), halogen, C 1-6 haloalkyl, C 1-6 perhaloalkyl, C 1-6 haloalkoxy, —CN, —C(═Z)R 30 , —C(═Z)OR 30 , —C(═Z)NR 31 R 32 , —C(R 30 )═NR 31 , —NR 31 R 32 , —N═CR 31 R 32 , —N(R 30 )—C(═Z)R 30 , —N(R 30 )—C(═Z)NR 31 R 32 , —S(O)NR 31 R 32 , —S(O) 2 NR 31 R 32 , —N(R 30 )—S(═O)R 30 , —N(R 30 )—S(═O) 2 R 30 , —OR 30 ), —SR 30 , and —OC(═Z)R 30 ; wherein said alkyl, alkenyl, alkynyl, cycloalkyl and alkoxy are optionally substituted; 
 or two of R 5 , R 6 , R 7 , and R 8  on adjacent carbons taken together, along with the two intervening carbons to which they are attached, form a C 3-6 cycloalkenyl, aryl, heteroaryl or C 3-6 heterocycloalkenyl group 
 R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  are each separately and independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl(C 3-6 cycloalkyl), halogen, C 1-6 haloalkyl, C 1-6 perhaloalkyl, C 1-6 haloalkoxy, —CN, —C(═Z)R 30 , —C(═Z)OR 30 , —C(═Z)NR 31 R 32 , —C(R 30 )═NR 31 , —NR 31 R 32 , —N═CR 31 R 32 , —N(R 30 )—C(═Z)R 30 , —N(R 30 )—C(═Z)NR 31 R 32 , —S(O)NR 31 R 32 , —S(O) 2 NR 31 R 32 , —N(R 30 )—S(═O)R 30 , —N(R 30 )—S(═O) 2 R 30 , —OR 30 ), —SR 30 , and —OC(═Z)R 30 ; wherein said alkyl, alkenyl, alkynyl, cykloalkyl and alkoxy is optionally substituted; 
 or two geminal R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  taken together, along with the carbon atom to which they are attached, form a carbonyl group; 
 or two geminal R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  taken together, along with the carbon atom to which they are attached, form a C 3-6 cycloalkyl or C 2-6 heterocycloalkyl group; 
 or two geminal R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  taken together, along with the carbon atom to which they are attached, form a C 2-6 alkylidene group 
 or two R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  on adjacent carbons, taken together along with the two intervening carbon atoms to which they are attached, form a double bond; 
 or one of R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  and the carbon atom to which it is attached and the carbon atom to which one adjacent R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  is attached, form a C 3-6 cycloalkyl or C 2-6 heterocycloalkyl group, provided that one or more of R 10 -R 16  is not present to complete the octet of all carbon atoms; 
 or one of R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  and the carbon atom to which it is attached and the carbon atom to which one non-adjacent R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  is attached, taken together with all intervening carbon atoms, form a C 3-6 cycloalkyl or C 2-6 heterocycloalkyl group, provided that one or more of R 10 -R 16  is not present to complete the octet of all carbon atoms; 
 or one of R 5 , R 6 , R 7 , and R 8  and the carbon atom to which it is attached and the carbon atom to which one of R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  is attached and at least two intervening carbon atoms, or one of R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  and the carbon atom to which it is attached and the carbon atom to which one of R 5 , R 6 , R 7 , and R 8  is attached and at least two intervening carbon atoms, form a C 5-7 cycloalkenyl or C 4-7 heterocycloalkyl group, provided that one or more of R 5 -R 16  is not present to complete the octet of all carbon atoms; 
 Z is oxygen or sulfur; and 
 R 30 , R 31  and R 32  are each independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 2-6 heteroalicyclyl; 
 or R 31  and R 32  taken together, along with the nitrogen atom to which they are attached, form a heterocycloalkyl group; 
 or R 31  and R 32  taken together, along with the carbon atom to which they are attached, form a C 3-6 cycloalkyl or heterocycloalkyl group. 
 
     
     
       2. The compound of  claim 1 , wherein the optionally substituted substituents for R 1 -R 16  are each independently substituted with a substituent selected from the group consisting of —CN, halogen, haloalkyl, —O(C 1-6 alkyl), —NR 31 R 32 , —S(C 1-6 alkyl), —O(C 1-6 haloalkyl). 
     
     
       3. The compound of  claim 1 , wherein X is oxygen or sulfur. 
     
     
       4. The compound of  claim 1 , wherein R 1 , R 2 , R 3 , and R 4  are each separately and independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 alkyl(C 3-6 cycloalkyl), halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 haloalkoxy, —CN, —C(═Z)R 30 , —C(═Z)OR 30 , —C(═Z)NR 31 R 32 , —C(R 30 )═NR 31 , —NR 31 R 32 , and —N═CR 31 R 32 . 
     
     
       5. The compound of  claim 1 , wherein R 1 , R 2 , R 3 , and R 4  are each selected from the group consisting of hydrogen, fluoro, and chloro. 
     
     
       6. The compound of  claim 1 , wherein R 5 , R 6 , R 7 , and R 8  are each separately and independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 alkyl(C 3-6 cycloalkyl), halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 haloalkoxy, —CN, —C(═Z)R 30 , —C(═Z)OR 30 , —C(═Z)NR 31 R 32 , —C(R 30 )═NR 31 , —NR 31 R 32 , and —N═CR 31 R 32 . 
     
     
       7. The compound of  claim 1 , wherein R 5 , R 6 , R 7 , and R 8  are each selected from the group consisting of hydrogen and fluoro. 
     
     
       8. The compound of  claim 1 , wherein R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  are each separately and independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 alkyl(C 3-6 cycloalkyl), halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 haloalkoxy, —CN, —C(═Z)R 30 , —C(═Z)OR 30 , —C(═Z)NR 31 R 32 , —C(R 30 )═NR 31 , —NR 31 R 32 , and —N═CR 31 R 32 . 
     
     
       9. The compound of  claim 1 , wherein R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  are each selected from the group consisting of hydrogen and fluoro. 
     
     
       10. The compound of  claim 1 , wherein two of R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  on adjacent carbons taken together, along with the two intervening carbon atoms to which they are attached, form a double bond. 
     
     
       11. The compound of  claim 1 , wherein R 20  is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, and haloalkyl. 
     
     
       12. The compound of  claim 1 , wherein R 20  is selected from the group consisting of hydrogen and methyl. 
     
     
       13. The compound of  claim 1 , wherein n is 2 or 3. 
     
     
       14. The compound of  claim 1 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       15. A pharmaceutical composition comprising one or more compounds of  claim 1  and a pharmaceutically acceptable diluents, excipient, or carrier.